1. Technical Field of the Invention
The present invention relates to the formulation of pro-penetrating agents which act in synergy, for preparing solutions for dermatological/cosmetic ungual and peri-ungual applications, and to the solutions resulting therefrom.
2. Description of Background and/or Related and/or Prior Art
The nails can be afflicted with disorders, deficiencies or pathologies of diverse nature and origin (Baran R. et. al., Diseases of the Nails and Their Management,. 3rd Edition, 2001). Mention may, for example, be made of paronychias, the causes of which may be bacterial, fungal, parasitic or viral or derived from dermatological or systemic diseases, or else may originate from a drug treatment. The fungal pathologies can be located specifically within the nail, such as onychomycosis, or else, like herpes or syphilis, affect other parts of the body, but can also have an effect on the physiology of the nail. Fungal infections of the nails are commonly caused by dermatophytes, but can also be caused by moulds, fungi and yeast.
The treatments used today are either local treatments or treatments given generally, and the two are often combined for optimum effectiveness. In fact, in order for a treatment to be effective, it must be long in order to observe the amount of time for a nail to regrow. In addition, mycoses can be located in the nail or in the nail bed, which requires that the active agent penetrate the nail in its entirety.
Treatments given generally often have adverse side effects and topical treatments are often less effective alone due to the difficult penetration through the nail.
Nail varnishes or film-forming solutions are, today, more particularly used for the treatment of onychomycosis and of similar fungal infections of the nails in humans, or mammals. Many compositions containing active agents with antifungal activity are described in the literature for the prevention and treatment of these conditions, such as, for example, 1-hydroxy-2-pyridone in a water-insoluble film-forming agent (U.S. Pat. No. 4,957,730), an active agent in a composition containing a 2-n-nonyl-1,3-dioxolane as pro-penetrating agent (WO 99/39680), terbinafine (U.S. Pat. No. 6,214,360), itraconazole (U.S. Pat. No. 4,267,179), amorolfine HCl (EP 0 389 778) or tioconazole (U.S. Pat. No. 5,916,545).
The effectiveness of a nail varnish as a delivery vehicle, for topical application of an active agent, has been described by Marty in J. Eur. Acad. Dermatol. Venerol., 4 (suppl. 1), S17-S21, (1995). This is the study of the delivery of an antifungal agent, amorolfine HCl. The varnish-based combination, consisting of a solvent, a plasticizer and a film-forming agent, as described in the literature does not unfortunately allow optimum penetration of the active agent into the nail.
It therefore is seen to be essential to develop a dermatological or cosmetic composition of the type such as a solution for ungual and peri-ungual application, which allows better penetration of the active agents through the nail, consequently providing better effectiveness of the active agents and a decrease in application time.
The use of urea as a keratolytic agent is, today, known practice. It has also been the subject of studies regarding its pro-penetrating power through the skin (Wohlrab W., J. Appl. Cosmetol., 9,1-7 (Jan. March 1991)) and also in the nail in combination with mercaptans (U.S. Pat. No. 5,696,164). A combination comprising urea as keratolytic agent and N-(2-mercaptopropionyl)glycine is described by Malhotra G. G. and Zatz J. L. (J. Pharm. Sciences, vol. 91, 2, (2002)), as providing very good penetration of the active agent into the nail.
No prior art describes the use of an acid or of ethoxydiglycol as a pro-penetrating agent in a solution for ungual and peri-ungual applications. In addition, the compositions described in the prior art would not motivate one skilled in this art to mix urea and an acid, or urea and ethoxydiglycol, in order to prepare a solution for ungual and peri-ungual applications in which the mixture has a synergistic effect on the penetration of the active agent through the nail.